((−)-2-exo-morpholinoisoborne-10-thiol, abbreviated as “(−)-MITH” and classified as a γ-aminothiol ligand, is an efficient catalyst that induces the stereoselective formation of chiral carbon centers in certain reactions (J. Org. Chem. 2006, 71, 833-835). (−)-MITH (CAS No. 874896-16-9) has the systematic name ((1R,2R,4R)-7,7-dimethyl-2-morpholino-bicyclo[2.2.1]heptan-1-yl)methanethiol and the structure:

The abbreviation MITH is used herein to apply to (−)-MITH and its enantiomer (+)-MITH ((+)-2-exo-morpholinoisoborne-10-thiol). It is particularly useful as a chiral catalyst in organozinc addition reactions to α-ketoesters and aldehydes, including methylation, ethylation, vinylation, propargylation, and arylation (see J. Org. Chem. 2006, 71, 833-835; Chem. Asian J. 2012, 7, 2921-2924; J. Org. Chem. 2007, 72, 5935-5937; Tetrahedron: Asymmetry 2009, 20, 1837-1841; J. Org. Chem. 2008, 73, 6445-6447; U.S. Pat. No. 8,168,835; U.S. Pat. Appl. 2011/0269955).
MITH has demonstrated utility for inducing high stereoselectivity in asymmetric carbon-carbon bond-forming reactions. However, its physical properties (i.e., non-solid oily form and instability under ambient conditions) and the reported method for its synthesis significantly limit its manufacture on large enough scales to be useful in the pharmaceutical industry. The synthesis of MITH that is disclosed in the peer-reviewed literature involves six formal reaction steps and various work-up and purification steps to access the product from the commercially available starting material, camphorsulfonic acid (see FIG. 1 and J. Org. Chem. 2006, 71, 833-835). Although the synthetic route itself is efficient, giving a 25% overall yield, the synthetic route is not suitable for scale-up for manufacture. Scale-up is unsuitable for a number of reasons, including those specified above.
For instance, triphenylphosphine is required to reduce a sulfonyl chloride intermediate to the desired thiol (A-2 in FIG. 1). The removal of the phosphine oxide byproduct of this reaction was problematic and multiple recrystallizations of A-2 followed by column chromatographic purification were required.
Scale-up is further complicated by the need for protection and deprotection steps. Owing to the high reactivity of the thiol intermediate A-2, the thiol functional group was protected as a benzyl thioether (A-3 in FIG. 1). Benzyl thioethers are difficult to deprotect to recover the thiol compound, and harsh reaction conditions were required in the final deprotection step. The use of a Birch reduction reaction in the deprotection step requires the handling of sodium metal and its dissolution in liquid ammonia. Sodium is flammable upon contact with moisture, water, acids and protic solvents such as alcohols, making scale-up potentially hazardous. Furthermore, ammonia boils at −33° C., and very low temperatures (−78° C.) are required to prevent dangerous pressure build-up. The use of such conditions should be avoided on manufacturing scales for safety concerns.
In addition, the need for multiple column purification operations limits suitability for scale-up. The known synthetic route requires the use of six chromatographic purifications steps (see J. Org. Chem. 2006, 71, 833-835). The product itself is also an oil and is purified by column chromatography. For manufacturing, purification of organic compounds using column chromatography typically results in higher production costs due to the increases in required time and materials as compared to other purification methods. Large volumes of organic solvents must be recycled or disposed, which has environmental and monetary costs. A chromatography-free process for the synthesis of MITH and MITH analogs would therefore be highly advantageous, expanding the utility of MITH as a catalytic or stoichiometric reagent in the pharmaceutical and chemical industries.
U.S. Pat. Appl. 2011/0269955 disclosed a synthetic route including the use of a morpholino sulfonamide functional group as a masked thiol in place of the previously used benzyl protecting group. This allowed for a direct, one-step conversion of the final intermediate B-6 to the thiol (i.e., MITH) using LiAlH4 as a reducing agent (FIG. 2). Although the synthesis provided improved scalability by removing the dangerous deprotection step in the original method, the overall yield was lower (20%). Furthermore, the method disclosed in U.S. Pat. Appl. 2011/0269955 is still problematic from an industrial perspective due to: i) the UV-transparency of all synthetic intermediates bearing morpholinosulfonamide substituents, which prevents reaction monitoring by ordinary UV-HPLC. Reaction monitoring is very important during manufacturing as it allows in-process control which ensures effective control of reaction leading to reproducible yields and product quality; ii) the need for purification of several intermediates by column chromatography; and iii) the large quantity of lithium aluminum hydride used in the final reduction step, the handling of which is particularly dangerous on manufacturing scales due to its extremely pyrophoric nature.
Moreover, organic compounds such as MITH that are oils rather than solids present certain disadvantages during manufacturing, including: i) they are often less stable than solids and can therefore require less convenient long-term storage conditions, such as in an inert atmosphere and/or at low temperatures, and ii) they are more difficult to transfer from one vessel to another vessel, such as is required for charging reagents into reactors. MITH is only stable for a period of days to weeks under ambient conditions. A solid, preferably crystalline, form of MITH or a MITH analog would be highly advantageous since it would be more stable, easier to transport and store, and easier to handle in industrial-scale chemical transformations.
Given the foregoing, it is clear that there is an unmet need for a convenient, safe, and scalable manufacturing process for MITH and related compounds. The present invention addresses this and other needs.